Dottorato in BIOLOGIA CELLULARE E DELLO SVILUPPO

Titolo della tesi: Relevance of KDM5B isoforms in breast cancer

KDM5B (also known as JARID1B or PLU-1) is a histone lysine demethylase involved in differentiation processes, gene expression regulation, DNA damage repair, cancer genesis, and drug resistance. Aberrant KDM5B expression has been observed in many human cancers. Intriguingly, growing evidence suggests that KDM5B can have a dual role, acting as an oncogene or as a tumor suppressor in a cell-specific context. KDM5B sustains cell proliferation in the luminal breast cancer cell line MCF7, while inhibits cell migration and invasion in the basal breast cancer cell line MDA-MB-231. Recently, it has been reported that an isoform of KDM5B including the variant exon- 6, namely RBP2H1, might contribute to tumor progression in melanoma. However, if different KDM5B isoforms could play a role in breast cancer subtypes has not been investigated. In this study, we are reporting the characterization of a new KDM5B isoform which is N-terminal truncated (KDM5B-NTT) and catalytically inactive. KDM5B-NTT is a splicing variant having a transcriptional start site downstream to that known for the canonical PLU-1 isoform and including also 36 additional residues encoded by the variant exon-6, previously associated to the RBP2H1 isoform in melanoma. We observed that KDM5B-NTT accumulates in breast cancer cells due to higher protein stability compared to KDM5B-PLU-1 and appears relatively more expressed in MDA- MB-231 than in MCF7. The exogenous over-expression of KDM5B-NTT in MCF7 cells correlates with a global increase of H3K4me3 levels and with the up-regulation of the tumor suppressor Caveolin-1 and genes related to the interferon-alpha and - gamma response. These results give rise to the possibility of further exploring the regulatory roles of KDM5B independent of its catalytic activity.